Ketamine for depression: A collection of key papers

This collection of papers is posted here to make them easily accessible for psychiatrists considering this form of treatment.

Dr David Straton. MBChB, DPM, FRANZCP.
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An intriguing pair of case reports.

One patient had an 18 month history of depression unsuccessfully treated with Citalopram, Mirtazapine, Venlafaxine and ECT. She was given a 5 day IV infusion of Ketamine at 0.27 mg/kg/hr. Her BDI improved from 36 to 11 in four days and she remained well 12 months later on Citalopram 40 mg.

The second patient had a 16 year history of depression unsuccessfully treated with Fluoxetine, Nefazadone, Mirtazapine, Venlafaxine, Amisulpride, Lithium and ECT. He was given a 5 day IV infusion of Ketamine at 0.3 mg/kg/hr. His BDI improved from 52 to 9 in four days. He relapsed twice, after 2.5 months and 8.5 months and had two further 5-day inf
usions which were successful. At 12 months he remained well on Lithium 500mg/day.

A randomized, placebo-controlled, double-blind crossover study of 18 patients with treatment resistant major depression, given a single intravenous infusion of Ketamine 0.5 mg/kg over 40 minutes. 71% met response criteria the day following ketamine infusion as compared with 0% of subjects treated with placebo.

A 55-year-old male subject with a treatment-resistant major depression and a co-occurring alcohol and benzodiazepine dependence received an intravenous infusion of 0.5 mg/kg ketamine over a period of 50 minutes.

Over the previous five years the subject had been treated with a wide variety of antidepressants: citalopram (40 mg/d), paroxetine (40 mg/d), mianserine (120 mg/d), mirtazapine (30 mg/d), venlafaxine (375 mg/d), trimipramine (350 mg/d), trazodone (900 mg/d), and escitalopram (20 mg/d). Augmentation therapy had comprised methylphenidate, valproic acid, lithium, olanzapine, quetiapine, buspirone, and chlorprothixene. Throughout 2002 the subject had received cognitive behavioural therapy in a day clinic. All psychopharmacological and psychotherapeutic interventions were tolerated well, but failed to achieve remission.

After the ketamine infusion, his BDI improved from 26 to 9 in two days.

An opportunistic case report of a woman with severe treatment-resistant depression who was refered for ECT shortly after ceasing anti-epileptic drugs. She was given ketamine as an anaesthetic for the ECT, but failed to have a convulsion, on two occasions. In spite of this she experienced an immediate and unexpected improvement in her mood both times.

Methods: Seven subjects with major depression completed 2 test days that involved intravenous treatment with ketamine hydrochloride (.5 mg/kg) or saline solutions under randomized, double-blind conditions.

Results: Subjects with depression evidenced significant improvement in depressive symptoms within 72 hours after ketamine but not placebo infusion (i.e., mean 25-item Hamilton Depression Rating Scale scores decreased by 14 ± SD 10 points vs. 0 ± 12 points, respectively during active and sham treatment).

Conclusions: These results suggest a potential role for NMDA receptor-modulating drugs in the treatment of depression.

General Papers on Glutamate, Ketamine, Mood and Safety

NMDA receptor antagonists ketamine and Ro25-6981 inhibit evoked release of glutamate in vivo in the subiculum
TL Stan, A Alvarsson, N Branzell, VC Sousa and P Svenningsson
Translational Psychiatry (2014) 4, e395

Abstract
Preclinical and clinical data have identified ketamine, a non-selective NMDAR (N-methyl-D-aspartate receptor) antagonist, as a promising medication for patients who do not respond to treatment with monoamine-based antidepressants. Moreover, unlike the current monoamine-based antidepressants, ketamine has a long-lasting effect already after a single dose. The mechanisms of ketamine action remain to be fully understood. Using a recently developed microelectrode array (MEA), which allows sub-second measurements of fluctuating glutamate concentrations, we studied here the effects of in vivo local application of the ketamine and of the N2B subunit-specific antagonist Ro25-6981 upon evoked glutamate release. Both ligands inhibit glutamate release in subregions of the hippocampus and prefrontal cortex. Likewise, acute systemic ketamine treatment, at an antidepressant dose, caused a reduction in evoked glutamate release in the subiculum. We suggest that the effects of ketamine and Ro25-6981 in the subiculum could involve blockade of presynaptic NMDA receptors containing N2B subunits. Pdf

Synaptic Dysfunction in Depression: Potential Therapeutic Targets
Ronald S. Duman and George K. Aghajanian
Science 5 Oct 2012: Vol 338, Number 6103. Pp 68-72.

Abstract
Basic and clinical studies demonstrate that depression is associated with reduced size of brain regions that regulate mood and cognition, including the prefrontal cortex and the hippocampus, and decreased neuronal synapses in these areas. Antidepressants can block or reverse these neuronal deficits, although typical antidepressants have limited efficacy and delayed response times of weeks to months. A notable recent discovery shows that ketamine, a N-methyl-d-aspartate receptor antagonist, produces rapid (within hours) antidepressant responses in patients who are resistant to typical antidepressants. Basic studies show that ketamine rapidly induces synaptogenesis and reverses the synaptic deficits caused by chronic stress. These findings highlight the central importance of homeostatic control of mood circuit connections and form the basis of a synaptogenic hypothesis of depression and treatment response. Pdf

Targeting the glutamatergic system to develop novel, improved therapeutics for mood disorders
Gerard Sanacora, Carlos A Zarate, John H Krystal, Husseini K Manji (Department of Psychiatry, Yale University School of Medicine)
Nature reviews. Drug discovery (Nat Rev Drug Discov) Vol. 7 Issue 5 Pg. 426-37 (May 2008) Pdf

This comprehensive 2008 review by major figures at Yale University and the National Institute of Mental Health discusses the theoretical basis for using the glutamate system for treating mood disorders. Comments about ketamine include (refs in the original):

'Clinically, ketamine is a popular agent for emergency department procedural sedation in children, with ample evidence to support its safety and efficacy. Although its psychotomimetic side effects have led to its misuse and abuse, there is no evidence that ketamine causes physical dependence in humans. In addition, recent studies found no evidence that repeated, albeit limited (typically less than four exposures), exposure to ketamine increases the risk of more severe or more protracted psychosis, perceptual changes resembling dissociation, severe emotional distress or euphoria in healthy subjects or in patient populations.'

'Ketamine is of particular interest because it has been shown to bring about rapid and relatively sustained antidepressant effects. Its rapid, robust and consistently reproducible antidepressant effects offer a unique opportunity to better delineate the precise cellular mechanisms involved.'

Psychiatric safety of ketamine in psychopharmacology research
Perry, Edward; Cramer, Joyce; Cho, Hyun-Sang; Petrakis, Ismene; Karper, Laurence; Genovese, Angelina; O'Donnell, Elizabeth; Krystal, John; D'Souza, D. & Yale Ketamine Study Group
Psychopharmacology. Volume 192, Number 2 / June, 2007 Pdf

'Four hundred and fifty subjects received at least one dose of active ketamine. Eight hundred and thirty three active ketamine and 621 placebo infusions were administered. Ten adverse mental status events were documented in nine subjects/infusions that were deemed related to ketamine administration (2% of subjects, 1.45% of infusions). All but one adverse reaction resolved by the end of the test session. The side effects in the remaining individual were no longer clinically significant within 4 days of the test session. No residual sequelae were observed.

Conclusion. Ketamine administration at subanesthetic doses appears to present an acceptable level of risk for carefully screened populations of healthy human subjects in the context of clinical research programs that intensively monitor subjects throughout their study participation.'

Subanesthetic ketamine: how it alters physiology and behavior in humans.
Rowland LM. Aviat Space Environ Med 2005; 76(7, Suppl.):C52–8. Pdf

'Its rapid onset, strong safety characteristics, and dose-dependent impact on psychotomimetic symptoms argue in favor of its continued use and application in clinical, investigative, and military settings.'

Clinical studies implementing glutamate neurotransmission in mood disorders.
Sanacora G, Rothman DL, Mason G, Krystal JH.
Ann N Y Acad Sci. 2003 Nov;1003:292-308. Pdf

Glutamate and psychiatric disorders
Eva M. Tsapakis & Michael J. Travis
Advances in Psychiatric Treatment (2002), vol. 8, pp. 189–197
http://apt.rcpsych.org/cgi/reprint/8/3/189

Long-term outcome of patients who receive ketamine during research
Adrienne C. Lahti, Dale Warfela, Tamara Michaelidisa, Martin A. Weilera, Kristin Freya and Carol A. Tammingaa
Biological Psychiatry. Volume 49, Issue 10, 15 May 2001, Pages 869-875
http://tinyurl.com/3wtqjc

'Results: There were no serious adverse events in more than 90 ketamine interviews. Distress to patients was minimal, which is shown by the lack of anxiety ratings. Over a mean follow-up period of 8 months, we found no differences between patients who did and did not receive ketamine on any measures of psychopathology, psychiatric care, or the amount of antipsychotic medication.

Conclusions: In a controlled environment and paying close attention to subject safety features, administering subanesthetic doses of ketamine causes no adverse events and little distress to schizophrenic volunteers. This study strongly indicates that administering ketamine does not change any aspect of the course of schizophrenic illness.'

Ketamine for Pain

Subanesthetic Ketamine Infusion Therapy: A Retrospective Analysis of a Novel Therapeutic Approach to Complex Regional Pain Syndrome
Correll, G. E.; Maleki, J.; Gracely, E. J.; Muir, J. J.; Harbut, R. E.
Pain Practice. 5(3):275-276, September 2005. Pdf

Case notes of 33 patients whose CRPS pain was treated by the inpatient administration of a continuous subanesthetic intravenous infusion of ketamine were reviewed. The dose and duration of ketamine therapy and the degree and duration of relief obtained were recorded. Notable side effects were also recorded.

Ketamine in Chronic Pain Management: An Evidence-Based Review
Graham Hocking, and Michael J. Cousins, Anesth Analg 2003;97:1730 –9. Pdf

The role of Ketamine in the management of chronic pain
Polly M. Edmonds. CME Bulletin Palliative Medicine • Volume 1 No. 1 • 1998 Pdf

Safety and Efficacy of Prolonged Outpatient Ketamine Infusions for Neuropathic Pain.
American Journal of Therapeutics. 13(4):300-305, July/August 2006.
Webster, Lynn R.; Walker, Mary Jean
http://tinyurl.com/4s36lr

This document is a consolidation of the information about the mechanisms and regulations that allow patients to access unapproved medicines or medical devices in Australia.

Non Medical Use of Ketamine